Frontotemporal dementia spreads via connected brain networks

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Dementia is a devastating and life-altering symptom that normally affects individuals who are aged 65 or over.

‘Frontotemporal dementia’ (FTD), a rarer cause of dementia compared to Alzheimer’s Disease, is a group of disorders named after the regions of the brain that are mainly affected (the frontal and temporal lobes) by the loss of brain cells, or neurons. It is often diagnosed between the ages of 45 and 60, making it all the more concerning for the general public.

As is the case with all types of dementia, FTD develops slowly, over a period of several years. However, the biological basis underlying disease progression is yet to be unveiled. The diversity of FTD and its various subtypes has rendered this a particularly difficult puzzle to solve. For example, some forms of the disease that mainly affect language, whilst others alter behaviour. Fortunately, research efforts have focused more attention on understanding the mechanisms underlying the disease, with the hope to develop therapeutic interventions for affected individuals.

A recent publication in Neuron from the University of California aims to understand cell death progression in FTD.

Previous research by the senior author of the article, William Seeley, MD and professor of Neurology and Pathology at the Memory and Aging Center and Weill Institute, shows that neurodegeneration in conditions such as FTD does not spread evenly in all directions as is the case with tumours. Instead, it appears that cell death follows a pattern according to brain regions that are functionally and synaptically connected, collectively termed “brain networks.”

The new study continues this line of investigation by exploring whether maps of brain connectivity can be used to predict the spread of cell death in individuals with FTD over the course of a year.

Two sets of patients with different types of FTD were recruited for the study: 42 individuals with behavioural variant FTD (mainly resulting in problems with social behaviour) and 30 individuals with semantic variant primary progressive aphasia (mainly influencing language).

The patients underwent two MRI scans. The first, conducted at the beginning of the experiment, showed the extent of degeneration that had already taken place for each individual. The second, taken a year later, measured progression of the disease over time. Averaged brain connectivity maps were created to show how 175 different brain regions were functionally related to each other, using functional MRI scans from 75 healthy participants.

Based on the idea that cell death in FTD begins at a particular location in the brain and spreads via networks to other regions, these maps were used to estimate the source of degeneration for each patient. This was done by matching the pattern of cell death to a brain network map, and establishing the network’s central hub as the likely source of degeneration for the patient. The researchers then evaluated how accurate their predictions were regarding progression of disease for each patient based on these network maps.

They found that two measures of connectivity improved their predictions of how likely a region was of experiencing cell death. First, the number of synaptic connections that separated the estimated centre of degeneration for the patient and the region in question. Second, the number of brain regions connected to the region in question that were experiencing cell death.

Lead author of the study and Assistant Professor of Neurology at the UCSF Memory and Aging Center and Weill Institute for Neurosciences, explained: “It’s like with an infectious disease, where your chances of becoming infected can be predicted by how many degrees of separation you have from ‘Patient Zero’ but also by how many people in your immediate social network are already sick”

In accordance with Seeley’s previous research, in some cases, the disease was found to only affect regions that were within a particular brain network, rather than spreading to all regions adjacent to an impacted location.

While there is not yet enough evidence for the method to go to clinical trials, the findings published by the group are promising.

Being able to predict disease progression for each patient could not only permit for therapeutic intervention to be catered to the individual, but could also allow for clinicians to effectively assess treatment options in altering disease progression, and help prepare patients and their families for the symptoms likely to arise.

“Just like epidemiologists rely on models of how infectious diseases spread to develop interventions targeted to key hubs or choke points,” Brown said, “Neurologists need to understand the underlying biological mechanisms of neurodegeneration to develop ways of slowing or halting the spread of the disease.”